Diastereoselective alkylation of α-amino-substituted benzyllithiums

Article abstract of DOI:10.1016/S0040-4039(00)01898-0

Reductive lithiation of a distereoisomeric mixture of bicyclic oxazolidines followed by reaction with alkyl halides afforded aminoalcohols in a highly syn-selective fashion. Reductive lithiation occurs with racemization at the benzylic carbon atom; the observed diastereoselectivities are rationalized in terms of a pair of rapidly equilibrating diastereoisomeric organolithium intermediates, one of which reacts preferentially under appropriate reaction conditions.

Full text of DOI:10.1016/S0040-4039(00)01898-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 129–131
Diastereoselective alkylation of a-amino-substituted
benzyllithiums
Ugo Azzena,* Luciano Pilo and Elisabetta Piras
Dipartimento di Chimica e Facolta` di Farmacia, Universita` di Sassari, via Vienna 2, I-07100 Sassari, Italy
Received 29 August 2000; revised 17 October 2000; accepted 26 October 2000
Abstract—Reductive lithiation of a distereoisomeric mixture of bicyclic oxazolidines followed by reaction with alkyl halides
afforded aminoalcohols in a highly syn-selective fashion. Reductive lithiation occurs with racemization at the benzylic carbon
atom; the observed diastereoselectivities are rationalized in terms of a pair of rapidly equilibrating diastereoisomeric organo-
lithium intermediates, one of which reacts preferentially under appropriate reaction conditions. © 2000 Elsevier Science Ltd. All
rights reserved.
bearing an oxyanionic group, was more stable under
The configurational stability of chiral a-substituted
the reaction conditions than a similar monolithium
arylmethyl organometallic reagents and their ability to
derivative generated from an open chain substrate
react with electrophiles in a stereodefined manner is a
(Scheme 1).10
topic of current interest in organic chemistry.1–5 Inves-
tigations on the carbolithiation of cinnamyl alcohol and
We ascribed this finding to intramolecular coordination
derivatives have shown that appropriately positioned
of the carbanionic moiety with the alkoxy group,11 and
substituents are sometimes able to coordinate to the
wish to report that reductive lithiation of a distereoiso-
organometallic center, fixing its configuration and al-
meric mixture of a bicyclic 2-phenyl-1,3-oxazolidine 1,
followed by alkylation, allows the highly diastereoselec-
lowing a diastereoselective alkylation.6–9
tive synthesis of N-(a-alkyl-substituted)benzyl-2-hy-
Whilst investigating the generation of a-amino-substi-
droxymethylpiperidines 5–7 (Scheme 2).
tuted benzyllithiums by reductive lithiation of cyclic
and open chain a-N,N-dialkylamino-substituted benzyl
alkyl ethers, we observed that a dilithium derivative
Results and discussion
generated from an oxazolidine, i.e. an organolithium
Oxazolidine 1 was obtained in 83% yield as a 92:8
Li
OLi
O
mixture of diastereoisomers according to a known pro-
cedure;12 1H NMR nOe difference spectra allowed us to
ascribe the syn configuration to the prevailing
diastereoisomer. Reaction of oxazolidine 1 with Li
powder (5 equiv.) in the presence of a catalytic amount
of naphthalene (10 mol%) in THF at −20°C for 4 h
quantitatively afforded, after aqueous work up, the
corresponding aminoalcohol 3 (Table 1, entry 1).
2 Li
Ph
Ph
stable at 0°C
N
N
THF
CH3
CH3
Bu
O
Li
2 Li
Ph
Ph
CH3
CH3
slowly protonated at 0°C
N
N
THF
CH3
CH3
Quenching the reaction mixture with electrophiles dif-
ferent from H2O resulted in the formation of
diastereoisomeric aminoalcohols 4a/4b–7a/7b. Quanti-
tative formation of intermediate dilithium derivative(s)
2 was evidenced as quenching the reaction mixture with
D2O: aminoalcohols 4a/4b were obtained in a 52:48
diastereoisomeric ratio (Table 1, entry 2); quenching
the reaction mixture with t-BuOD or with 2,6-
Scheme 1. Reductive lithiation of a-N,N-dialkyl-substituted
benzyl alkyl ethers.
Keywords: carbanions; diastereoselectivity; lithium and compounds;
reduction.
* Corresponding author. Tel.: +39079229549; fax: +39079229559;
e-mail: ugo@ssmain.uniss.it
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01898-0

130
U. Azzena et al. / Tetrahedron Letters 42 (2001) 129–131
LiO
HO
HO
Li
E
E
O
Li, THF
1. EX
2. H2O
+
N
Ph
N
Ph
N
Ph
N
Ph
-20°C, 4h
2
3, 4a/4b-7a/7b
1, 92:8 mixture of
diastereoisomers
Scheme 2. Reductive lithiation of oxazolidine 1.
Table 1. Reductive lithiation and reaction with electrophiles of oxazolidine 1
Entry
EX
T (°C)a
Product, E=
Yield (%)b
Diastereoisomeric ratio, a/bc
1
2
3
4
5
6
7
8
9
H2O
D2O
−20
−20
−20
−20
−80
−20
−20
−20
−20
−20
0
3, H
4a/4b, D
4a/4b, D
4a/4b, D
\95
\95
\95
\95
\95
74e
–
52:48d
55:45d
56:44d
55:45d
93:7
t-BuOD
2,6-(CH3)3CC6H3OD
D2O
PhCH2Cl
C6H13Br
C4H9I
C4H9Br
C4H9Cl
C4H9Cl
4a/4b, D
5a/5b, PhCH2
6a/6b, C6H13
7a/7b, C4H9
7a/7b, C4H9
7a/7b, C4H9
7a/7b, C4H9
50e
\95:B5
\95:B5
\95:B5
63:37
57e
56
10
11
B5f
23g
67:33
a All reactions run at −20°C for 4 h; the electrophile was added at the temperature reported and the mixture stirred for 15 min before aqueous
work-up. For a general procedure see Ref. 10
b As determined by 1H NMR spectroscopy, unless otherwise indicated.
c As determined by GC-MS, unless otherwise indicated.
d As determined by 1H NMR spectroscopy.
e Isolated yield.
f \90% of 3 was also detected.
g 72% of 3 was also detected.
(CH3)3CC6H3OD, or lowering the reaction temperature
to −80°C prior to quenching, did not affect this result
(Table 1, entries 3–5).
that reductive lithiation of oxazolidine 1 affords an
essentially planar organolithium intermediate, which
reacts stereoselectively with alkylating reagents and non
stereoselectively with deuterating agents. This hypothe-
sis appears to us relatively unlikely, due to the results
obtained in the synthesis of aminoalcohols 7a/7b, where
C4H9I and C4H9Br afford higher diastereoselectivities
than the less reactive C4H9Cl.
At variance with the above results, reductive cleavage
followed by reaction with PhCH2Cl, C6H13Br, C4H9I or
C4H9Br afforded aminoalcohols 5a/5b, 6a/6b and 7a/7b,
respectively, in satisfactory yields and good diastereose-
lectivities (Table 1, entries 6–9). However, low yields of
aminoalcohols 7a/7b, and low diastereoselectivities were
observed quenching the reaction mixture with C4H9Cl
(Table 1, entries 10 and 11).
We can alternatively assume that reductive lithiation of
oxazolidine 1 occurs with racemization at the benzylic
carbon atom, giving rise to a pair of rapidly intercon-
verting diastereoisomeric organolithium intermediates
2a/2b, one of which reacts preferentially and in a
stereodefined way (either under retention or inversion
of configuration) under appropriate reaction conditions
(Scheme 4).1,2
To determine the relative stereochemistry of the reduc-
tive alkylation products, aminoalcohols 7a/7b were syn-
thesized by reacting oxazolidine 1 with C4H9MgBr;
indeed, reaction of Grignard reagents with N-substi-
tuted-2-aryl-1,3-oxazolidines is reported to occur with
an overall prevailing inversion of configuration at the
electrophilic carbon.13–16 Under the new conditions,
aminoalcohols 7a/7b were obtained in 32% yield; the
diastereoselectivity of this reaction (30:70, as deter-
mined by GC-MS) is opposite to that obtained in the
reductive alkylation procedure (Scheme 3). We there-
fore ascribe the anti configuration to aminoalcohol 7b
and the syn configuration to aminoalcohol 7a, as well
as to aminoalcohols 5a and 6a.
HO
HO
Bu
Bu
O
i or ii
+
N
Ph
N
Ph
N
Ph
1
7a
7b
Scheme 3. Syntheses of diastereoisomeric alcohols 7a/7b: i: 1.
Li, THF, −20°C; 2. BuBr, then H2O: 7a/7b= >95:<5; ii:
BuMgBr, THF, −20°C, then H2O: 7a/7b=30:70.
The results obtained could be rationalized assuming

U. Azzena et al. / Tetrahedron Letters 42 (2001) 129–131
131
HO
LiO
LiO
E
Li
Li
Li, THF
1. alkylX
2. H2O
N
Ph
N
Ph
N
Ph
1
-20°C, 4h
2a, syn
2b, anti
5a-7a
Scheme 4. Epimerization and kinetic resolution of 2a/2b.
Racemization is supported not only by the results of
deuteration experiments, but also by the reaction mech-
anism commonly accepted for the reductive cleavage of
benzylic carbonꢀoxygen bonds, which occurs via inter-
mediate configurationally labile benzylic radicals.17
3. Ahlbrecht, H.; Harbach, J.; Hoffmann, R. W.; Ruhland,
T. Liebigs Ann. Chem. 1995, 211–216.
4. Hoffmann, R. W.; Ru¨hl, T.; Chemla, F.; Zahneisen, T.
Liebigs Ann. Chem. 1992, 719–724.
5. Hoffmann, R. W.; Ru¨hl, T.; Harbach, J. Liebigs Ann.
Chem. 1992, 725–730.
6. Mu¨ck-Lichtenfeld, C.; Ahlbrecht, H. Tetrahedron 1999,
55, 2609–2624.
7. Mu¨ck-Lichtenfeld, C.; Ahlbrecht, H. Tetrahedron 1996,
52, 10025–10042.
8. Klein, S.; Marek, I.; Normant, J.-F. J. Org. Chem. 1994,
59, 2925–2926.
9. Kato, T.; Marumoto, S.; Sato, T.; Kuwajima, I. Synlett
1990, 671–672.
10. Azzena, U.; Pilo, L.; Piras, E. Tetrahedron 2000, 56,
3775–3780.
11. Weiss, E. Angew. Chem., Int. Ed. Engl. 1993, 32, 1501–
1523.
We propose that deuteriation of the rapidly equilibrat-
ing intermediates requires an activation energy lower
than (or comparable to) the activation energy of their
epimerization, whilst a relatively high activation energy
can be hypothesized for the alkylation step. This as-
sumption is supported by the low reactivity of the
organolithium(s) toward C4H9Cl, which eventually ren-
ders a less stereospecific alkylation step. Indeed, it has
been reported that activation barriers for retentive and
inverse electrophilic attack at benzyllithiums should not
differ very much.18
12. Kasuga, S.; Taguchi, T. Chem. Pharm. Bull. 1965, 13,
233–240; the authors did not investigate the
diastereosiomeric distribution of reaction products.
13. Takahashi, H.; Chida, Y.; Higashiyama, K.; Onishi, H.
Chem. Pharm. Bull. 1985, 33, 4662–4670.
In summary, we have shown an additional useful fea-
ture of the reductive lithiation of 2-aryl-substituted
oxygen heterocycles, i.e. the possibility to turn into
intramolecular coordination and, as a consequence,
into a highly diastereoselective reaction, the contempo-
rary generation of a carbanionic and an oxyanionic
center by a reductive cleavage procedure. Further work
is in progress to extend the scope of this methodology.
14. Takahashi, H.; Hsieh, B. C.; Higashiyama, K. Chem.
Pharm. Bull. 1990, 38, 2429–2434.
15. Yamato, M.; Hashigaki, K.; Ishikawa, S.; Qais, N. Tetra-
hedron Lett. 1988, 29, 6949–6950.
16. Neelakantan, L. J. Org. Chem. 1971, 36, 2256–2260; see
also: Just, G.; Potvin, P.; Uggowitzer, P.; Bird, P. J. Org.
Chem. 1983, 48, 2923–2924.
17. Examples of configurationally stable Cr(CO)3-complexed
benzylic radicals were recently reported: Schmalz, H.-G.;
de Koning, C. B.; Bernicke, D.; Siegel, S.; Pfletschinger,
A. Angew. Chem., Int. Ed. Engl. 1999, 38, 1620–1623.
18. Jemmins, E. D.; Chandrasekhar, J.; Schleyer, P. v. R. J.
Am. Chem. Soc. 1979, 101, 527–533; see also Ref. 6.
References
1. Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 2282–2316.
2. Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayu-
manavan, S. Acc. Chem. Res. 1996, 29, 552–560.
.